Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

The table below summarises the geometric issues observed across the polymeric chains and their fit to the electron density.The red, orange, yellow and green segments of the lower bar indicate the fraction of residues that contain outliers for >=3, 2, 1 and 0 types of geometric quality criteria respectively.A grey segment represents the fraction of residues that are not modelled.The numeric value for each fraction is indicated below the corresponding segment, with a dot representing fractions <=5% The upper red bar (where present) indicates the fraction of residues that have poor fit to the electron density.The numeric value is given above the bar.

Mol Chain Length
Quality of chain 2 Entry composition i ○ There are 3 unique types of molecules in this entry.The entry contains 4736 atoms, of which 0 are hydrogens and 0 are deuteriums.
In the tables below, the ZeroOcc column contains the number of atoms modelled with zero occupancy, the AltConf column contains the number of residues with at least one atom in alternate conformation and the Trace column contains the number of residues modelled with at most 2 atoms.
• Molecule 1 is a protein called Proto-oncogene tyrosine-protein kinase receptor Ret.  • Molecule 1: Proto-oncogene tyrosine-protein kinase receptor Ret Chain A:

Mol
• Molecule 1: Proto-oncogene tyrosine-protein kinase receptor Ret Chain B: Xtriage's analysis on translational NCS is as follows: The largest off-origin peak in the Patterson function is 5.33% of the height of the origin peak.No significant pseudotranslation is detected.
5 Model quality i ○

Standard geometry i ○
Bond lengths and bond angles in the following residue types are not validated in this section: Q4J The Z score for a bond length (or angle) is the number of standard deviations the observed value is removed from the expected value.A bond length (or angle) with |Z| > 5 is considered an outlier worth inspection.RMSZ is the root-mean-square of all Z scores of the bond lengths (or angles).There are no chirality outliers.

Mol Chain
There are no planarity outliers.

Too-close contacts i ○
In the following table, the Non-H and H(model) columns list the number of non-hydrogen atoms and hydrogen atoms in the chain respectively.The H(added) column lists the number of hydrogen atoms added and optimized by MolProbity.The Clashes column lists the number of clashes within the asymmetric unit, whereas Symm-Clashes lists symmetry-related clashes.The all-atom clashscore is defined as the number of clashes found per 1000 atoms (including hydrogen atoms).The all-atom clashscore for this structure is 0.
All (4) close contacts within the same asymmetric unit are listed below, sorted by their clash magnitude.
Atom There are no symmetry-related clashes.

Protein backbone i ○
In the following table, the Percentiles column shows the percent Ramachandran outliers of the chain as a percentile score with respect to all X-ray entries followed by that with respect to entries of similar resolution.
The Analysed column shows the number of residues for which the backbone conformation was analysed, and the total number of residues.In the following table, the Percentiles column shows the percent sidechain outliers of the chain as a percentile score with respect to all X-ray entries followed by that with respect to entries of similar resolution.

Mol
The Analysed column shows the number of residues for which the sidechain conformation was analysed, and the total number of residues.Sometimes sidechains can be flipped to improve hydrogen bonding and reduce clashes.There are no such sidechains identified.

RNA i ○
There are no RNA molecules in this entry.

Non-standard residues in protein, DNA, RNA chains i ○
There are no non-standard protein/DNA/RNA residues in this entry.

Carbohydrates i ○
There are no monosaccharides in this entry.

Ligand geometry i ○
3 ligands are modelled in this entry.
In the following The following is a two-dimensional graphical depiction of Mogul quality analysis of bond lengths, bond angles, torsion angles, and ring geometry for all instances of the Ligand of Interest.In addition, ligands with molecular weight > 250 and outliers as shown on the validation Tables will also be included.For torsion angles, if less then 5% of the Mogul distribution of torsion angles is within 10 degrees of the torsion angle in question, then that torsion angle is considered an outlier.
Any bond that is central to one or more torsion angles identified as an outlier by Mogul will be highlighted in the graph.For rings, the root-mean-square deviation (RMSD) between the ring in question and similar rings identified by Mogul is calculated over all ring torsion angles.If the average RMSD is greater than 60 degrees and the minimal RMSD between the ring in question and any Mogul-identified rings is also greater than 60 degrees, then that ring is considered an outlier.The outliers are highlighted in purple.The color gray indicates Mogul did not find sufficient equivalents in the CSD to analyse the geometry.
Ligand Q4J A 1101 (B) Bond lengths Bond angles Torsions Rings

Other polymers i ○
There are no such residues in this entry.

Polymer linkage issues i ○
There are no chain breaks in this entry.7DU9 There are no non-standard protein/DNA/RNA residues in this entry.

Carbohydrates i ○
There are no monosaccharides in this entry.

Ligands i ○
In the following table, the Atoms column lists the number of modelled atoms in the group and the number defined in the chemical component dictionary.The B-factors column lists the minimum, median, 95 th percentile and maximum values of B factors of atoms in the group.The column labelled 'Q< 0.9' lists the number of atoms with occupancy less than 0.9.The following is a graphical depiction of the model fit to experimental electron density of all instances of the Ligand of Interest.In addition, ligands with molecular weight > 250 and outliers as shown on the geometry validation Tables will also be included.Each fit is shown from different orientation to approximate a three-dimensional view.7DU9

Other polymers i ○
There are no such residues in this entry.
property plots i ○ These plots are drawn for all protein, RNA, DNA and oligosaccharide chains in the entry.The first graphic for a chain summarises the proportions of the various outlier classes displayed in the second graphic.The second graphic shows the sequence view annotated by issues in geometry and electron density.Residues are color-coded according to the number of geometric quality criteria for which they contain at least one outlier: green = 0, yellow = 1, orange = 2 and red = 3 or more.A red dot above a residue indicates a poor fit to the electron density (RSRZ > 2).Stretches of 2 or more consecutive residues without any outlier are shown as a green connector.Residues present in the sample, but not in the model, are shown in grey.
table, the Counts columns list the number of bonds (or angles) for which Mogul statistics could be retrieved, the number of bonds (or angles) that are observed in the model and the number of bonds (or angles) that are defined in the Chemical Component Dictionary.The Link column lists molecule types, if any, to which the group is linked.The Z score for a bond length (or angle) is the number of standard deviations the observed value is removed from the expected value.A bond length (or angle) with |Z| > 2 is considered an outlier worth inspection.RMSZ is the root-mean-square of all Z scores of the bond lengths (or angles).In the following table, the Chirals column lists the number of chiral outliers, the number of chiral centers analysed, the number of these observed in the model and the number defined in the Chemical Component Dictionary.Similar counts are reported in the Torsion and Rings columns.'-' means no outliers of that kind were identified.
Continued from previous page... Non-standard residues in protein, DNA, RNA chains i ○